Drug-drug and drug-disease interactions contribute to the variability in response observed when a patient population is treated with standard doses of drugs. Pharmacokinetic techniques provide a means to identify and quantitate such interactions, and to assess their potential clinical relevance. This research project will investigate certain drug-drug and drug-disease interactions which involve metabolized compounds, or agents commonly employed in patients with hepatic disorders. Individual protocols are designed with two major purposes-first, to provide data which will promote greater understanding of the mechanisms (physiologic, pharmacokinetic, or biochemical) responsible for drug-drug or drug-disease interactions. Second, to provide specific, clinically useful information about the relevance of certain drug interaction or disease interactions about which little or no information is available. Two areas which have been particularly selected for study are the effect of liver diseases and enzyme-inducing drugs on the bioavailability of high and low extraction ratio drugs, and the implications of disease-induced changes in plasma protein binding on drug distribution and clearance. Although most previous work has focused on problems of decreased bioavailability, porto-systemic shunting seen in cirrhosis can cause increases in the absorption of drugs normally undergoing substantial first pass metabolism. The influence of liver disease on the plasma protein binding of drugs, especially with respect to subsequent effects on distribution of clearance, has received little attention. Pharmacokinetic methods and compartmental modeling are particularly suitable to the analysis of such drug-drug and drug-disease interactions because they allow separate calculation and quantitation of the individual components of drug disposition (absorption, tissue distribution, renal and nonrenal clearance). Thus, an estimate of the magnitude of differences in these individual parameters can be made between normal and disease states, possible mechanisms can be identified, and predictions can be made about those clinical settings in which significant increases in toxicity of decreases in efficacy might be expected.